iNO = inhaled nitric oxide; LPD = low potassium dextran.Critical Care June 2002 Vol 6 No 3 Strüber The case report by Della Rocca and coworkers published in this issue of Critical Care [
Trang 1iNO = inhaled nitric oxide; LPD = low potassium dextran.
Critical Care June 2002 Vol 6 No 3 Strüber
The case report by Della Rocca and coworkers published in
this issue of Critical Care [1] describes the occurrence of
severe reperfusion injury after lung transplantation and
successful treatment using a combination of inhaled nitric
oxide (iNO) and surfactant instillation What is the role of
surfactant in management of initially impaired graft function
after lung transplantation, and do these findings apply to
other forms of lung injury?
Ischaemia/reperfusion injury leading to initial graft failure is a
major cause of early mortality after lung transplantation In
addition, this problem led to the exclusion of most organ
donors from lung harvesting, because acceptance criteria
selected only optimal grafts A shortage of suitable lung
grafts became the rate-limiting step to lung transplantation
[2] Numerous studies were performed to avoid or ameliorate
ischaemia/reperfusion injury As early as 1991, Novick and
coworkers [3] reported on alterations in surface activity of
surfactant in experimental lung transplantation Subsequent
work [4] revealed an increase in serum protein associated
with an increased small aggregate/large aggregate ratio in
lavage of transplanted lungs This finding led to the
hypothesis that leakage of plasma protein into the alveolar
space may inhibit surface-active large surfactant aggregates
In order to deal with this problem, two courses of action were
considered One is to substitute surface-active surfactant,
and the other is to prevent plasma protein leakage into the
alveolar space In 1995 we were the first to report successful clinical treatment of reperfusion injury in a lung transplant recipient by administration of exogenous surfactant [5], followed by a review of six consecutive patients with established severe ischaemia/reperfusion injury [6] Because
a prospective clinical trial of surfactant substitution in lung transplantation is not available, these clinical observations are supported only by animal studies [7]
Methods to prevent ischaemia/reperfusion injury and pulmonary oedema were the subject of numerous studies The use of iNO as a means to ameliorate such injury by reduction in pulmonary vascular resistance, leucocyte sequestration in the lung and improvement in gas exchange emerged from laboratory investigations [8] Therefore, many lung transplant programmes use iNO routinely during early reperfusion of the lung Bearing in mind that the concept of ischaemia/reperfusion injury in clinical transplantation also embodies the state of the donor lung before harvesting and the quality of preservation, the method of lung procurement must be considered
Antegrade cold flush perfusion using cold Euro-Collins solution became the standard method of lung procurement 10–15 years ago [9] Euro-Collins is a solution of intracellular ion composition that was originally developed for kidney preservation Deleterious effects of this solution on the
Commentary
What is the role of surfactant and inhaled nitric oxide in lung
transplantation?
Martin Strüber
Staff Surgeon, Hannover Thoracic Transplant Program, Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Germany
Correspondence: Martin Strüber, strueber@thg.mh-hannover.de
© 2002 BioMed Central Ltd (Print ISSN 1364-8535; Online ISSN 1466-609X)
Abstract
Although numerous studies over the past 40 years have addressed this problem, initial graft failure is
still a key question in clinical lung transplantation As a possible tool to avoid and treat initial graft failure
after lung transplantation, laboratory evidence and clinical reports currently emphasize the role of
substitution therapy of surfactant combined with inhaled nitric oxide
Keywords lung transplantation, nitric oxide, reperfusion injury, surfactant
Trang 2Available online http://ccforum.com/content/6/3/186
surfactant system were frequently reported [10]
Experimentally, it was shown that a preservation solution
composed of extracellular ions might improve early graft
function, particularly when dextran was added as an oncotic
agent The so-called low potassium dextran (LPD) solution
improved surfactant function in an ischaemia/reperfusion
model in minipigs by preventing plasma leakage [11] A
further improvement in graft function and better maintenance
of the small aggregate/large aggregate ratio was found when
the LPD solution was flushed retrograde through the graft
[12] Therefore, many major lung transplant centres
abandoned the Euro-Collins technique and started to use
LPD or other extracellular solutions instead A lesser
incidence as well as lesser severity of ischaemia/reperfusion
injury and a reduction in requirement for early
retransplantation have been reported [13,14]
The case reported by Della Rocca and coworkers [1]
represents a typical report of severe reperfusion injury in a
graft preserved in Euro-Collins solution, with an ischaemic
time of 6 hours or more In our experience, Euro-Collins
preserved lungs are especially prone to reperfusion injury
when extracorporeal circulation is used during the procedure
We observed a prolonged ventilation period in such patients
after lung transplantation as a result of reperfusion injury, and
we therefore changed the perfusion solution from
Euro-Collins to LPD (Fig 1) According to the case report [1],
extracorporeal circulation was instituted when right heart
failure occurred after implantation of the left lung and
clamping of the contralateral pulmonary artery, despite iNO
and prostaglandin E1treatment However, it does not
indicate for how long the first transplanted lung was
reperfused when the pulmonary artery was clamped
Increased pulmonary vascular resistance is a common
phenomenon in early reperfusion For this reason, many
surgeons prefer to transplant the right lung first, and to
employ a prolonged reperfusion time after implantation of the
first lung before clamping the contralateral pulmonary artery
There are case reports and small studies of the successful
use of iNO and surfactant replacement in adult respiratory
distress syndrome patients However, both therapeutic
strategies failed to show efficacy in prospective randomized
trials, so what justification is there for the use of these
approaches in lung transplantation? A body of evidence has
been established that indicates that surfactant function after
lung transplantation is reduced in all cases However, after an
uncomplicated lung transplant procedure, lung function starts
to improve following completion of surgery and is usually
best 3–6 months after transplantation In the cases of graft
failure, brain death and infection of the donor lung, reduced
surfactant function is aggravated by preservation of the graft,
ischaemia and reperfusion Therefore, substitution of
surfactant may bridge the patient to recovery of the graft The
combination of iNO and surfactant proved to be successful
in experimental severe reperfusion injury [15], strengthening
the hypothesis that this combination prevents intrapulmonary shunt more effectively than does either intervention alone, and that it reduces inactivation of surfactant substitutes
In summary, we emphasize that surfactant function should be considered when a preservation method is selected for lung procurement In addition, combined iNO and surfactant replacement may be effective in graft failure after lung transplantation, and should be used before indications for extracorporeal membrane oxygenation or retransplantation are considered This interesting approach was successful in the experimental setting of acute lung injury and needs to be verified in clinical indications other than lung transplantation
Competing interests
None declared
References
1 Della Rocca G, Pierconti F, Gabriella Costa M, Coccia C, Pompei
L, Rocco M, Venuta F, Pietropaoli P Severe reperfusion lung
injury after double lung transplantation Crit Care 2002,
6:240-244
2 Novick RJ: Innovative technique to enhance lung preservation
[editorial] J Thorac Cardiovasc Surg 2002, 123:3-5.
3 Novick RJ, Possmeyer F, Veldhuizen RAW, Menkis AH, McKenzie
FN: Surfactant analysis and replacement therapy: a future tool
of the lung transplant surgeon? Ann Thorac Surg 1991, 52:
1194-1200
4 Veldhuizen RA, Lee J, Sandler D, Hull W, Whitsett JA,Lewis J,
Possmayer F, Novick RJ: Alterations in pulmonary surfactant composition and activity after experimental lung
transplanta-tion Am Rev Respir Dis 1993, 148:218-233.
5 Strüber M, Cremer J, Harringer W, Hirt SW, Costard-Jackle A,
Haverich A: Nebulized synthetic surfactant in reperfusion
injury after single lung transplantation J Thorac Cardiovasc
Surg 1995, 110:563-564.
6 Strüber M, Hirt SW, Cremer J, Harringer W, Haverich A: Surfac-tant replacement in reperfusion injury after clinical lung
trans-plantation Intensive Care Med 1999, 25:862-864.
7 Hohlfeld JM, Strüber M, Ahlf K, Hoeper MM, Fraund S, Krug N,
Warnecke G, Harringer W, Haverich A, Fabel H: Exogenous
sur-Figure 1
Ventilation time in 54 patients after lung transplantation with and without use of extracorporeal circulation (ECC) In 28 recipients the lungs were preserved with Euro-Collins (EC) solution The remaining grafts were perfused with low potassium dextran (LPD) solution
0 50 100 150 200 250 300
LPD EC
Trang 3Critical Care June 2002 Vol 6 No 3 Strüber
factant improves survival and surfactant function in
ischaemia-reperfusion injury in minipigs Eur Respir J 1999,
13:1037-1043.
8 Strüber M, Harringer W, Ernst M, Morschheuser T, Hein M, Bund
M, Haverich A: Inhaled nitric oxide as a prophylactic treatment
against reperfusion injury of the lung Thorac Cardiovasc Surg
1999, 47:179-182.
9 Haverich A, Scott WC, Jamieson SW: Twenty years of lung
preservation: a review J Heart Transplant 1985, 4:234-240.
10 Andrade RS, Wangensteen OD, Jo JK, Tsai MY, Bolman RM III:
Effect of hypothermic pulmonary artery flushing on capillary
filtration coefficient Transplantation 2000, 70:267-271.
11 Strüber M, Hohlfeld JM, Fraund S, Kim P, Warnecke G, Haverich
A: Low-potassium dextran solution ameliorates reperfusion
injury of the lung and protects surfactant function J Thorac
Cardiovasc Surg 2000, 120:566-572.
12 Strüber M, Hohlfeld JM, Kofidis T, Warnecke G, Niedermeyer J,
Sommer SP, Haverich A: Surfactant function in lung transplan-tation after 24 hours of ischemia: advantage of retrograde
flush perfusion for preservation J Thorac Cardiovasc Surg
2002, 123:98-103.
13 Fischer S, Matte-Martyn A, De Perrot M, Waddell TK, Sekine Y,
Hutcheon M, Keshavjee S: Low-potassium dextran preserva-tion solupreserva-tion improves lung funcpreserva-tion after human lung
trans-plantation J Thorac Cardiovasc Surg 2001, 121:594—596.
14 Strüber M, Wilhelmi M, Harringer W, Niedermeyer J, Anssar M,
Kunsebeck A, Schmitto JD, Haverich A: Flush perfusion with low potassium dextran solution improves early graft function
in clinical lung transplantation Eur J Cardiothorac Surg 2001,
19:190-194.
15 Warnecke G, Strüber M, Fraud S, Hohlfeld JM, Haverich A: Com-bined exogenous surfactant and inhaled nitric oxide therapy
for lung ischemia-reperfusion injury in minipigs
Transplanta-tion 2001, 71:1238-1244.